Effects of Chlorinated Dibenzodioxins - ACS Symposium Series (ACS

Chapter 5

Effects of Chlorinated Dibenzodioxins Renate D. Kimbrough and Vernon N. Houk

Downloaded by UNIV LAVAL on July 12, 2016 | http://pubs.acs.org Publication Date: April 24, 1987 | doi: 10.1021/bk-1987-0338.ch005

Center for Environmental Health, Centers for Disease Control, Public Health Service, U.S. Department of Health and Human Services, Atlanta, GA 30333

This paper is a review of the reported effects of 2,3,7,8-tetrachlorodibenzodioxin (TCDD) on the health of workers in chemical plants and on the general population. Virtually no information exists on the human health effects of other congeners of polychlorinated dibenzodioxins (PCDDs). Most exposures associated with acute health effects have been occupational, particularly those occurring when reaction vessels have exploded during the production of 2,4,5trichloro-phenol. Symptoms of 2,3,7,8-TCDD exposure are chloracne, severe fatigue, nervousness, and decreased libido. In addition, workers may complain of weakness, loss of appetite, sleep disturbances, and a sensory neuropathy. In two factories, porphyria cutanea tarda was reported in workers. It is not clear, however, whether this illness was caused by the TCDD and/or by hexachlorobenzene and other chemicals, which were also present in the plants. Follow-up studies of highly exposed workers indicated that chloracne was the most persistent health effect. Upon cessation of exposure, many of the other abnormalities either decreased in severity or subsided completely. In a few isolated incidences, members of the general population have been exposed to significant levels of TCDD. In one such episode in Seveso, Italy, the systemic illness was mild and apparently short-lived. In another episode, a child had a hemorrhagic cystitis, and a few others had chloracne. Both of these symptoms subsided. No convincing chronic health effects have been reported. In case-control studies, an association has been made between soft-tissue sarcoma and exposure to phenoxy herbicides that contained TCDD. Subsequent studies, however, have cast some doubt on these findings, and further studies are needed. There are 75 isomers of chlorinated dibenzodioxins (PCDDs). They vary greatly in toxic ity. The most toxic isomer is the 2,3,7,8-tetrachlorodibenzodioxin (2,3,7,8-TCDD). Other isomers, in which at least three of the 2,3,7,8 positions are occupied by halogens, are also quite active biologically. Most of what we know about the toxicity of these chemicals was developed from animal studies, and most studies conducted were done with the 2,3,7,8-TCDD. Different species respond quite differently to the toxic effects of 2,3,7,8-TCDD. The hamster, This chapter not subject to U.S. copyright. Published 1987, American Chemical Society

Exner; Solving Hazardous Waste Problems ACS Symposium Series; American Chemical Society: Washington, DC, 1987.

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for instance, appears to be 1,000 times less sensitive to the toxic effects of 2,3,7,8 TCDD than i s the guinea p i g . The s e n s i t i v i t y of humans to 2,3,7,8-TCDD i s s t i l l unknown. From animal studies we have learned that 2,3,7,8-TCDD causes l i v e r t o x i c i t y , affects the skin, depresses the cell-mediated immune response, affects reproduction and c e l l d i f f e r e n t i a t i o n , and produces cancers i n rats and mice (1). But the target organs i n d i f f e r e n t animal species vary and, except f o r the skin and, perhaps, the l i v e r , i t i s not clear what other health effects these chemicals may have i n humans. I t i s also unclear what health effects the other PCDDs might have singly or i n combination.


Sources PCDDs are accidentally formed during the production of chlorinated phenols and related products (2-5). They may also be formed during the burning process i n incinerators and through other forms of combustion, such as motor vehicles. The 2,3,7,8-TCDD i s usually a minor component of these combustion products. They have been i d e n t i f i e d i n urban dust, i n gasoline motor o i l , and i n d i e s e l motor o i l (Ballschmiter, K.; Buchert, H.; Niemczy, K. R.; Munder, A.; Swerrev, M. Chemosphere i n press 1986.) Thus, these chemicals are ubiquitous i n our environment i n very low concentrations and have been i d e n t i f i e d i n f i s h , lake sediments, human adipose tissue, and milk (6-10). In addition, waste from the production of chlorinated phenols, i f poorly controlled, may lead to heavier contamination i n l o c a l areas (11). Human health effects Exposure to PCDDs may occur i n the occupational as well as the general environment. The general population i s usually exposed to lower levels than workers. For this reason, workers are the ones primarily examined f o r acute and chronic health e f f e c t s , unless subgroups of the general population for some reason have higher exposures.(12). For most of the PCDDs no information on human health effects i s available except that during the production of pentachlorophenol workers have developed a skin disease, chloracne (13) and complaints such as neuralgic pain i n the lower extremities, and symptoms such as persistent bronchitis, and eye i r r i t a t i o n (14). The bronchitis seems to be more prevalent i n workers exposed to technical pentachlorophenol than i n those exposed to the other chlorinated phenols. Humans with a history of exposure to 2,3,7,8-TCDD have been studied most often. Therefore, I w i l l devote most of the rest of this paper to a review of these studies. Although exposure to other PCDDs may be as prevalent or more prevalent i n the general population, we have no information on the human health e f f e c t s of the other PCDDs. Workers can be exposed to PCDDs during the manufacture of an i n d u s t r i a l product, while mixing ingredients f o r a commercial product, or when packaging the commercial product. The doses that these d i f f e r e n t populations receive vary widely. Occasionally,



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maintenance workers and cleanup crews may receive high exposures to such chemicals, which could be avoided through the use of approp r i a t e gear and the practice of good personal hygiene. Another hazard i s peculiar to 2,3,7,8 TCDD. During the production of 2,4,5-trichlorophenol, an exothermic reaction can occur, causing the reaction vessel to explode. This has happened at several production f a c i l i t i e s . In almost a l l of these incidents workers were heavily exposed to 2,3,7,8 TCDD during the cleanup (15-20). Chloracne has developed in the workers, and, i n some instances, acute systemic disease. (Chloracne i s a skin disease which consists of small skin-colored cysts with a central opening and of blackheads). Chloracne i s produced either by d i r e c t contact with the chemical on the skin or as an expression of a systemic disease. Another group of chemicals, the chlorinated biphenyls and the chlorinated dibenzofurans, also produce chloracne. Two outbreaks of poisoning by these chemicals occurred i n the general population i n Japan and Taiwan. In both instances, the offending chemicals were ingested and generalized chloracne developed i n the patients. The c l i n i c a l features of chloracne, regardless of the type of chemical causing i t , have been most consistent. The most d i s t i n c t i v e cutaneous lesion i s a skin-colored cyst that measures from 1 to 10 mm i n diameter, with a central opening. The other dominant lesion i s the comedo. Usually these lesions start over the maxillary bone, then involve the entire face and the neck. Lesions may also be present on the back, arms, legs, and other areas of the body. Large pustules may form because of secondary infection. In areas exposed to sunlight, a photosensitivity-type reaction may occur. Conjunctivitis, with swelling of the eyelids and other f a c i a l skin, may precede the chloracne. Once chloracne has developed, i t may be active f o r many years. Often, secondary infections occur, leaving deep-pitted, permanent scars. In addition to chloracne, acute or chronic health e f f e c t s , or both, may occur. Acute e f f e c t s are noticed soon after heavy exposure to TCDD, as after the explosions (21). In such cases, workers usually become i l l within 1 week. If workers are continually exposed to lower levels of TCDD, however, signs of i l l n e s s may not occur f o r several months. Under such circumstances, the overriding sign i s the chloracne. Although i n Nitro, West V i r g i n i a exposure and occupational i l l n e s s occurred as early as 1947, i t was not u n t i l 195 7 that TCDD was i d e n t i f i e d as the c u l p r i t (19). Dermatologists have conducted most investigations of acute poisoning episodes, and t h e i r reports primarily focus on the skin lesions. Whether, occasionally, i l l n e s s without chloracne may occur in exposed individuals i s , at present, a matter of debate. In these outbreaks, some workers had severe chloracne without any systemic e f f e c t s . On the other hand, ailments involving the skin, the eyes, the l i v e r , the nervous system, and, occasionally, the heart were observed i n other workers. The eye-related problems included c o n j u n c t i v i t i s (inflammation of the conjunctiva) and b l e p h a r i t i s (inflammation of the e y e l i d s ) .



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In addition to the chloracne, hyperpigmentation and hirsutism (increased hair growth) were also reported. The l i v e r i s most consistently affected i n severe acute 2,3,7,8TCDD poisoning. Goldmann et a l . (15) described morphological changes i n a l i v e r biopsy from an affected worker as mild subacute h e p a t i t i s with focal areas of hyaline. The hepatocytes were enlarged, with moderately sized l i p i d vacuoles i n t h e i r cytoplasm. A gray pigment that did not stain p o s i t i v e f o r iron was noted. Many patients also had a sensory neuropathy (functional and/or pathological changes i n the nervous system). In addition to the neuropathy, neurasthenia (functional nervous d e b i l i t y ) has been associated with acute 2,3,7,8-TCDD poisoning. Complaints related to neurasthenia have been sleep disturbances, decreased l i b i d o , impotence, lack of drive, and mood changes. Unfortunately, these types of complaints cannot be objectively substantiated. They are often the types of complaints associated with aging or with depression and thus they are d i f f i c u l t to evaluate. In many instances, the skin lesions were quite d i s f i g u r i n g , and t h i s may have caused a depression i n some patients. Paresthesias (abnormal sensations such as burning p r i c k l i n g ) , headache, muscle pain, and leg weakness have been described i n workers acutely exposed to 2,3,7,8-TCDD. Loss of appetite and diarrhea were occasionally observed. Most of the other organs did not seem to be affected. In contrast, May (16), reported a poisoning outbreak i n which workers suffered severe chloracne but had no other obvious systemic i l l n e s s e s . In the only poisoning outbreak i n which humans (three chemists) were exposed solely to 2,3,7,8-TCDD, chloracne developed i n two patients (22), and they had hyperpigmentation, increasing fatigue, and a tendency to have headaches. One patient complained that his skin was excessively o i l y . One of these patients l o s t about 6.5 kg of weight and reported excessive fatigue and loss of vigor. He also had excessive hair growth (hirsutism). About 1 year l a t e r , serum cholesterol levels f o r a l l three were raised, but c l i n i c a l laboratory tests showed no other abnormalities. These chemists had been synthesizing 2,3,7,8-TCDD, an a c t i v i t y that poses the greatest hazard of exposure for chemists. Patients who showed an increase i n t o t a l serum l i p i d s have also been described by Jirasek et a l . (23) and PazderovaVejlupkova et a l . (24). Many of these patients had abnormal results for glucose tolerance tests, hepatic lesions, increased alpha-1 and gamma globulin i n plasma, and decreased plasma albumin. Hypercholesteremia and polyneuropathy were quite prevalent. In two f a c t o r i e s , i n addition to chloracne, porphria cutanea tarda (a disturbance of porphyrin metabolism characterized by chronic skin lesions ranging from s l i g h t skin f r a g i l i t y to severe chronic scarring, by enlarged l i v e r s and by excessive urinary excretion of uroporphyrin and coproporphyria. Uroporphyrin and coproporphyrin are iron-free c y c l i c tetrapyrrole derivatives) developed i n the workers, (23,25). The p o s s i b i l i t y of simultaneous exposure to hexachlorobenzene, however, cannot be excluded. Hexachlorobenzene may be a contaminant i n the production of



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pentachlorophenol. In the episode described by Jirasek et a l . (23), pentachlorophenol was also produced, and four patients with severe porphyria cutanea tarda also had hirsutism but did not have chloracne, this was similar to the reaction of patients who had been poisoned by hexachlorobenzene (26,27.). In many of these f a c t o r i e s , follow-up studies were conducted (15,17 ,24,28-31). Pazderova-Vejlupkova et a l . (24) studied 55 exposed workers 10 years after their i l l n e s s e s began. Most workers' health had improved. Their serum l i p i d levels did not s i g n i f i c a n t l y d i f f e r from those of the controls. Their serum alpha and gamma globulins had normalized, but elevated mean values of t o t a l blood protein were s t i l l present. Increased concentrations of porphryins were no longer present i n urine, skin mainfestations normally seen with porphyria cutanea tarda were rare, and results of l i v e r function tests had improved. In the l i v e r biopsies, even for the most severe forms of poisoning, only mild steatosis or p e r i p o r t a l f i b r o s i s were noted. In 1947 at a Nitro, West V i r g i n i a , plant an explosion occurred during the manufacture of 2,4,5-trichlorophenol. The accident was reevaluated i n 1984 (30). Chloracne s t i l l persisted i n 55.7% of the workers. Other investigators have also noted this extreme persistence of chloracne (24,28). Regarding systemic health e f f e c t s , not much was found. Hypertension, angina, coronary artery disease, skin cancer, and cancers of a l l s i t e s were not s i g n i f i c a n t l y associated with exposure. Among those who had been exposed, 59.1% had a c t i n i c elastosis (degeneration of e l a s t i c tissue i n the skin caused by those rays of l i g h t beyond the v i o l e t end of the spectrum that produce chemical e f f e c t s ) , i n contrast to 30.1% among the controls. The laboratory findings were e s s e n t i a l l y within the normal range. After adjustment for age and smoking, the results of nerve-conduction tests for the controls and the exposed groups d i d not d i f f e r . The pulmonary function values among those who were exposed and who currently smoked, however, were lower than values f o r those who were not exposed and who did not smoke. Moses et a l . (32) studied a portion of the same cohort that had been reexamined by Suskind and Hertzberg (30). In 1979, 226 workers were examined and chloracne was s t i l l present i n 52%. The chloracne i n many of these workers had persisted for 26 years; i n 29 workers, i t had persisted for 30 years. These workers also showed elevated gamma glutamyl transpeptidase. The mean gamma glutamyl transpeptidase was higher i n workers with chloracne than i n those without. This survey revealed no other findings of note. The difference i n the results between the follow-up by Moses et a l . and the one by Suskind and Hertzberg can be explained, i n part, by the difference i n the composition of the cohorts. May (29), conducted a similar study 10 years after an explosion i n a factory i n which chloracne developed i n 79 workers, and found that only half of the affected workers s t i l l had chloracne. No other adverse health effects were noted that could be related to the previous exposure. The mortality data for these d i f f e r e n t groups did not indicate any obvious trends. However, Thiess et a l . (18) reexamined 74 persons whom Goldmann (15) had previously studied. These workers



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had been exposed to TCDD during an uncontrolled reaction at a trichlorophenol f a c i l i t y several decades e a r l i e r . The o v e r a l l mortality rate of 21 deaths did not d i f f e r i n this group from the rate expected i n three external reference populations or from that observed i n two international comparison groups. Of the 21 deceased persons, 7 had cancer, compared with an expected 4.1 rate. Three of these deaths were due to stomach cancer, compared with an expected rate of O.6. This expected rate was obtained from regional mortality data. One stomach cancer occurred among 148 individuals i n the two comparison cohorts. If t h i s p a r t i c u l a r study by Thiess et a l . i s c a r e f u l l y reviewed, a number of problems become obvious. One i s the choice of the comparison groups. An additional problem i s the fact that the number of deaths (19) i s so small. We need additional studies with more participants and more c a r e f u l l y selected comparison groups to c l a r i f y the observations made by Thiess et a l . Several such studies are i n progress. On the other hand, Hardell and Sandstrom (33) and Eriksson et a l . (34) conducted two case-control studies i n Sweden and reported an increased r i s k of s o f t - t i s s u e sarcomas (cancers of s o f t - t i s s u e ) i n men who were exposed to trichlorophenol or to phenoxy herbicides. In a t h i r d case-control study, investigators suggested that phenoxy herbicides and chlorophenols may also predispose to Hodgkin's lymphoma. Other sources however, provide l i t t l e support for t h i s theory (35). Recently, Coggon and Acheson summarized the Swedish studies (36.). They concluded: "Further research i s urgently needed to confirm or refute these associations, to define the extent of the r i s k ( i f any) and to i d e n t i f y the carcinogen(s)." The Swedish studies could not be substantiated by Milham (37). Preliminary results from a case-control study i n New Zealand have not indicated an excess r i s k of soft tissue sarcoma (38). We must kept i n mind, however, that the mortality rate for s o f t - t i s s u e sarcoma for U.S. males between the ages of 40 and 64 i s extremely low and ranges from about 5 to 20 per m i l l i o n . This low incidence severely l i m i t s the power i n some reported studies to detect such rare tumors. The r e s u l t s of work by Honchar and Halperin (39) and Cook (40) of the United States supported the Swedish studies. Honchar and Halperin (39) noted that i n four merged cohorts of exposed workers there were 105 deaths, 3 (2.9%) of which were due to s o f t - t i s s u e sarcoma. On the basis of national death rates for men age 20 to 80, only O.07% of the deaths due to soft tissue sarcoma would have been expected. After this was noted, however, another person i n one of the four cohorts was found to have a s o f t - t i s s u e sarcoma (40-42), which made a t o t a l of four s o f t - t i s s u e sarcomas. A review of tissue sections from these four tumors and from tumors of three additional cases gave some i n t e r e s t i n g r e s u l t s . Only two of the four cases with documented evidence of exposure and three additional cases, which did not have documented evidence of exposure, were confirmed to be soft tissue sarcomas (43). Thus, upon review by experts, not a l l of the tumors o r i g i n a l l y diagnosed as soft tissue sarcomas were found to be soft tissue sarcomas.


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Further studies w i l l have to be conducted to determine whether exposure to these types of chemicals are associated with a higher incidence of soft tissue sarcomas. A l l of these studies, i n which associations between exposure to TCDD and an increased incidence of soft tissue sarcoma were reported, involved workers who had either manufactured these compounds or had applied the herbicide 2,4,5-T. In a l l of these instances, however, the workers were exposed not only to TCDD but also to either chlorinated phenols or to phenoxy herbicides.


General Population Two poisoning outbreaks have occurred i n the general population. One was i n 1976 i n Seveso, I t a l y , when a reaction vessel i n a factory exploded (44.,45). The chemicals i n the vessel escaped into the a i r and descended as a cloud on the surrounding neighborhood. The chemicals were trichlorophenol, sodium trichlorophenate, ethylene g l y c o l , sodium hyrdroxide, and TCDD. The population l i v i n g adjacent to the plant was exposed to the cloud and l a t e r to contaminated vegetation. Two weeks after the incident, the people l i v i n g i n the contaminated area were evacuated. In t h i s s i t u a t i o n , the exposure levels i n the cloud were probably quite high. A few vegetation samples collected within the f i r s t 2 weeks after the incident contained up to 15 ppm (mg/kg) of TCDD. Thus, s i g n i f i c a n t exposures probably occurred during the f i r s t few weeks after the explosion. Within these f i r s t few weeks, 22 people (7 adults and 15 children aged 3 to 13) were hospitalized or admitted to outpatient c l i n i c s . A dermatitis that resembled f i r s t - a n d second-degree burns, with b l i s t e r s and, l a t e r , crusts developed i n these patients. In addition, lacrimation and the sensation of g r i t i n the the eyes were reported, but c o n j u n c t i v i t i s was not observed. These skin lesions healed within 2 to 3 months. Between 2 and 8 weeks after exposure, a number of patients developed blackheads and cysts of d i f f e r e n t sizes t y p i c a l of chloracne. These lesions started to appear as the other skin lesions were fading. In the f i r s t few days, g a s t r o i n t e s t i n a l disturbances were also noted. A number of patients had s l i g h t l y enlarged l i v e r s . In these cases, no evidence was detected of a p e r i p h e r i a l neuropathy or of an e f f e c t on the central nervous system. The immune response i n t h i s population was within the normal range. Since then, a number of health studies have been conducted in t h i s population (46). A small percentage of the children i n the area had chloracne. The number of cases ranged from 167-196, depending on whether very mild cases (which were not unequivocal chloracne) were included i n the count and at what time these counts were made. None of these cases were as d i s f i g u r i n g as cases observed in some of the workers discussed e a r l i e r . Although l i v e r problems, enlarged l i v e r s , and some abnormal results f o r l i v e r function tests were reported, when the o v e r a l l results of these studies were evaluated, no severe systemic health effects were noted (47,48)Another episode i n which a few people received substantial exposure to TCDD occurred i n Missouri. In 1971, waste from the production of hexachlorophene at a manufacturing f a c i l i t y i n



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southwestern Missouri was mixed with salvage o i l and sprayed on various s i t e s throughout the State f o r dust control (11,49). This waste had high concentrations of TCDD. The source of the TCDD waste was a plant where 2,4,5-trichloro-phenol was made f o r the production of hexachlorophene. The poisoning episode was f i r s t discovered when a 6-year-old g i r l from Lincoln County, Missouri, was admitted to St. Louis Children's Hospital with an acute hemorrhagic c y s t i t i s (inflammation of the urinary bladder with bleeding). The c h i l d had played i n the s o i l of a r i d i n g arena. Her f i r s t symptoms were headache, epistaxis (nose bleeds), diarrhea, and lethargy. She then had a hemorrhagic c y s t i t i s . Three other persons who had used the same riding arena complained of recurrent headaches, skin lesions, and polyarthralgia (pain i n more than one j o i n t ) . The concentration of TCDD i n the s o i l of this arena was 30 ppm, or 30 mg/kg. The child's acute symptoms subsided after a time (50). Chloracne developed i n two l i t t l e boys, who had played i n another contaminated r i d i n g arena, and adults associated with the arena complained of headaches. A p i l o t study was conducted i n a small group of people from another, more recently discovered, contaminated area i n Missouri (51) - This group's exposures were much lower. The s o i l contamination i n most areas was generally less than 1 ppm of TCDD (mg/kg). The group consisted of 68 people who were possibly exposed and 35 people who were presumably not exposed. There were no s t a t i s t i c a l l y s i g n i f i c a n t differences i n the test results between the two groups. Results of an additional study were reported recently (52) . In this study 154 exposed and 155 unexposed persons were examined. The exposed persons had been l i v i n g i n a mobile home park in which 2,3,7,8-TCDD contaminated waste o i l was sprayed f o r dust control. The TCDD contamination dated back to 1971 when TCDD-contaminated sludge wastes were taken from a hexachlorophene production f a c i l i t y (11,53.). Levels of 2,3,7,8-TCDD up to 2.2 ppm (mg/kg) were s t i l l present more than ten years l a t e r . No increased c l i n i c a l i l l n e s s was noted i n the group who had l i v e d i n the contaminated mobile home park. Some differences were noted, however, i n the immunological responses between the two groups. A l l persons were given a skin test to measure delayed-type hypersensitivity. Half of the results i n both groups could not be used because two of the four persons reading the skin tests apparently did not interpret the skin responses properly. Of the remaining participants, however, 11.8% i n the exposed group and 1.1% i n the control group were anergic (transient reduction or complete lack of r e a c t i v i t y to antigens or allergens). The r e l a t i v e anergy was noted i n 35.3% of the exposed group versus 11.8% of the control group. The exposed group had a n o n s t a t i s t i c a l increased frequency of abnormal T - c e l l subset test r e s u l t s . Many parameters can affect the results of these tests, such as age, psychological stress, alcohol consumption, malnutrition, and infectious agents (54). I t i s not clear, i n the absence of c l i n i c a l disease, what these results mean. Further studies are needed to confirm these findings. Ratios of subsets of lymphocytes may be



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affected by the t o t a l lymphocyte count. Apparently the exposed group had an elevated white blood c e l l count which was s t a t i s t i c a l l y significant. The concentration of 2,3,7,8-TCDD has now been measured i n the adipose tissue of 39 persons from Missouri with a history of r e s i d e n t i a l (19), recreational (5), or occupational (15) exposure, and 57 persons i n a control group. A l l participants had detectable levels of 2,3,7,8-TCDD, but the exposed group had s i g n i f i c a n t l y higher levels (p < O.001). Levels i n the controls ranged from 1.4- 20.2 ppt (ng/kg), i n the recreational group from 5.0-577 ppt (ng/kg), i n the r e s i d e n t i a l group from 2.8-59.1 ppt (ng/kg), and i n the occupationally exposed group from 3.5-750 ppt (ng/kg). The geometric means f o r the d i f f e r e n t groups were: controls 6.4 ppt (ng/kg), recreational 38.9 ppt (ng/kg), r e s i d e n t i a l 14.6 ppt (ng/kg), occupational 29.8 ppt (ng/kg). Residential exposure was defined as either l i v i n g i n close proximity to areas with 2,3,7,8 TCDD contaminated s o i l , or having evidence of contamination inside the home. Recreational exposure was defined of at least one time per week r i d i n g or caring for horses i n 2,3,7,8-TCDD contaminated stable arenas. Occupational exposure was defined as working i n a hexachlorophene production f a c i l i t y or at truck terminals where the grounds had been sprayed with 2,3,7,8 TCDD contaminated waste oil.(Patterson, D. G., J r . Ph.D., Hoffman, R. E., Needham, L. L., Roberts, D.W., Bagby, J . R., P i r k l e , J . L., Falk, H., Sampson, E. J . , Houk, V. N. JAMA i n press.) The preliminary findings suggest that people l i v i n g i n 2,3,7,8-TCDD contaminated areas may have s l i g h t l y higher body burdens than the general populations. I t i s possible that this i s unique to Missouri since 2,3,7,8-TCDD was mixed i n an o i l when applied to s o i l and r i d i n g arenas and has a greater b i o a v a i l a b i l i t y (55) than when mixed with s o i l from other areas (56). In the future these determinations w i l l help i n the assessment of exposure. In addition, a morbidity study was recently completed (Ranch Hand study) on p i l o t s who flew spraying missions i n Vietnam and on other A i r Force personnel. These members of the m i l i t a r y were exposed to Agent Orange, a mixture of the herbicides 2,4-D and 2, 4.5- T. The 2,4,5 T was contaminated with 2,3,7,8-TCDD, (57.). None of the findings were alarming. Findings d i f f e r e d only i n the occurrence of skin cancers (mostly basal c e l l carcinomas), which were s i g n i f i c a n t l y higher i n the Ranch Hand group when measured against the comparison group (p = O.03). Thirty-one basal c e l l carcinomas occurred among the Ranch Hand group and 21 among the comparison group. These results, however, have not been corrected f o r geographic area, ethnic backgrounds, and excessive exposure to sunlight. Preliminary analysis of f e r t i l i t y and reproduction suggests a clustering of b i r t h anomalies of the skin i n Ranch Handers* children. In addition, the neonatal death rate (p - O.02) was s i g n i f i c a n t l y increased for the Ranch Hand group. Before t h e i r exposure i n Southeast Asia, the Ranch Hand group had 20 newborn offspring who died, and the comparison group had 17. After their service i n Southeast Asia, however, the Ranch Hand group had 14 neonatal deaths and the comparison group had only 3. The Ranch



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Handers also had s i g n i f i c a n t d e f i c i t s i n two s p e c i f i c peripheral leg pulses and i n a l l leg pulses, as a group. Ranch Handers, i n addition, had elevated l i v e r enzyme levels and lower cholesterol levels. More Ranch Handers were found to have hepatomegaly (enlarged l i v e r ) and v e r i f i e d h i s t o r i e s of p r i o r hepatic disease than t h e i r counterparts. Additional data analysis and follow-up of the Ranch Handers may c l a r i f y some of the preliminary findings made i n t h i s cross-sectional study. None of these findings, however, could be related to herbicide exposure because no s p e c i f i c "dose-response effect'* could be shown. The retrospective assessment of exposure i n situations l i k e Ranch Hand i s extremely d i f f i c u l t , even i f the environment i s well defined and the exposure levels of a certain chemical are known. In an occupational situation, for instance, two people i n the same environment can, f o r a variety of reasons, receive d i f f e r e n t doses. The reasons include variations i n personal hygiene and i n the a b i l i t y to metabolize and excrete chemicals. For example, some investigators have found that workers who smoke have higher levels of chemicals i n t h e i r body f l u i d s than t h e i r nonsmoking counterparts. In a retrospective study such as t h i s , when the l a s t exposure to Agent Orange was at least 12 years ago, i t i s d i f f i c u l t to assess what effect other, l a t e r i n s u l t s may have had on the subjects* health. Furthermore, for purely s t a t i s t i c a l reasons, some differences w i l l be found i f many endpoints are examined. None of the findings i n the Ranch Hand study have been confirmed i n other studies. The Centers for Disease Control recently completed a case-control study to determine i f men who served i n the U.S. m i l i t a r y i n Vietnam have been at an increased r i s k of fathering babies with serious congenital malformations. (58). Again, no s t r i k i n g findings were made, and i t i s not r e a l l y clear whether this study should be more appropriately c l a s s i f i e d as a Vietnam experience study because of the great d i f f i c u l t i e s i n appropriately determining exposure to 2,3,7,8-TCDD i n Agent Orange. The same can be said for other anecdotal reports that have linked exposure to the herbicide 2,4,5-T to a variety of undesirable health e f f e c t s . Some of this information i s summarized by Reggiani (44). Since most of the reports are anecdotal, and on reexamination could not be v e r i f i e d , they w i l l not be reviewed here. In conclusion, the most prevalent lesion i n humans after acute exposure to 2,3,7,8-TCDD i s a skin lesion referred to as chloracne. This skin disease may be accompanied by hirsutism and hyperpigmentation. After acute exposure to toxic l e v e l s , l i v e r function may be impaired and a sensory neuropathy may be present. There may be complaints of weakness, weight loss, severe fatigue, and a general malaise. Many of these acute symptoms and signs revert to normal when exposure ceases. The chloracne i s probably the most persistent lesion. No convincing chronic human health e f f e c t s , other than chloracne, have been reported, nor i s the dose of 2,3,7,8-TCDD known that would cause systemic i l l n e s s or death i n humans. V i r t u a l l y no information i s available on other PCDD congeners.


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1987


Effects of Chlorinated Dibenzodioxins - ACS Symposium Series (ACS

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